title: Atypical hand-foot-mouth disease in children: a hospital-based prospective cohort study.
abstract: BACKGROUND
  In 2010, we observed children with atypical presentations of hand-foot-mouth disease (HFMD), such as rashes on earlobes and faces, or bullae on trunks and bilateral limbs. Hyperpigmentation later developed as the bullous lesions crusted. Thus, we intended to study the etiology of the illness and the phylogeny of the pathogens.
  
  
  METHODS
  Patients were prospectively enrolled in a tertiary medical center in Taipei, Taiwan. The definition of atypical HFMD includes symptoms of acute viral infection with either of the following presentations: (1) maculopapular rashes presenting on the trunks, buttocks or facial areas, or (2) large vesicles or bullae on any sites of the body. Patients were classified into two groups according to vesicle sizes by two pediatricians at different points in time. The large vesicle group was defined as having vesciculobullous lesions ≥ 1 cm in diameter; the small rashes group had maculopapular rashes < 1cm in diameter. Two throat swabs were collected from each patient for virus isolation and reverse transcription polymerase chain reactions.
  
  
  RESULTS
  We enrolled 101 patients between March and December 2010. The mean age of the participants was 3.3 ± 3.0 years (median age: 2.5 years, range: 21 days-13.5 years). The ratio of males to females was 1.8 to 1. All samples were enterovirus-positive, including coxsackievirus A6 (80%), coxsackievirus A16 (6%), enterovirus 71 (1%), coxsackievirus A5 (1%) and 12 non-typable enterovirus (12%). Bullous fluid aspirated from 2 patients also grew coxsackievirus A6. Among the patients infected with coxsackievirus A6, 54% (45/81) had bullae, compared to 25% (5/20) of those having non-coxsackievirus A6 infections (P=0.02). Fourteen cases had myoclonic jerks and one boy was diagnosed with febrile convulsions. None had complications or sequelae. Phylogenetic analysis showed the strains in Taiwan in 2010 shared more commonality with strains from Finland in 2009 (GenBank: FJ870502-FJ870508), and were close to those circulating in Japan in 2011 (GenBank: AB649286-AB649291).
  
  
  CONCLUSIONS
  Coxsackievirus A6 infections may cause atypical manifestations of HFMD, including vesicles or papules on faces or bullae on trunks. These features could provide valuable information to distinguish this versatile enterovirus infection from other virus-induced vesiculobullous diseases.
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wen-Chan
authors.initials: WC
authors.lastname: Huang
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Huang
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Lu
authors.forename: Ai-Ling
authors.initials: AL
authors.lastname: Cheng
authors.forename: Luan-Yin
authors.initials: LY
authors.lastname: Chang
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003875:Drug Eruptions / Q000209:etiology / Q000473:pathology; D004770:Enterovirus / Q000145:classification / Q000302:isolation & purification*; D005260:Female; D006232:Hand, Foot and Mouth Disease / Q000473:pathology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011446:Prospective Studies; D012872:Skin Diseases, Vesiculobullous / Q000209:etiology / Q000473:pathology; D013624:Taiwan; D062606:Tertiary Care Centers